The protean nature of the central nervous system tumors in NF2, incomplete understanding of their natural history, and undefined mechanism of symptom formation have resulted in a strategy of treating patients only after they develop neurologic deficits. By that time, tumors are typically large and neurological deficits irreversible. Surgical removal of large tumors often adds deficits. Better knowledge of NF2 natural history and tumor growth patterns could improve surgical timing and outcomes. We started a natural history study of NF2 patients 11 years ago to gain clinical and molecular insights into the effects of the type (missense, nonsense, deletion) of NF2 gene mutation on tumor development/progression and to identify features associated with symptom evolution in patients with NF2-associated tumors. The natural history study of NF2 initially enrolled 169 subjects, with the final subject completing follow-up evaluation in November 2018. This prospective natural history study identified factors that influenced tumor biology, symptom formation, and treatment outcome. Central nervous system tumors in NF2 usually contained many different populations of tumor cells. A saltatory growth pattern of periodic tumor growth was more often seen (59%) than linear (30%) or exponential growth (11%). Elevated intralabyrinthine protein and larger tumor size by MRI-scanning correlated with hearing loss. We published the first comprehensive whole exome sequencing study of NF2-related meningiomas. Sequencing of 2 adjacent intracranial meningiomas removed from the same patient showed that the second copy of the NF2 gene was inactivated in both tumors. The faster growing tumor, a Grade II meningioma, had a higher level of genomic instability than the slower-growing, Grade I meningioma. Long-term follow up of patients with NF2 was found to be essential in evaluating disease progression. However, because tumor growth and symptom production were unpredictable and new tumors developed in NF2 patients over their lifetime, we could not propose a better method for timing of tumor resection than the present practice of resecting only symptom-producing tumors. In February 2019, the study began enrollment of another 100 NF2 patients, who will undergo annual clinical and radiologic evaluations for 10 years as outpatients. Patients with NF2 have symptoms that significantly affect their lives, including hearing loss and speech/swallowing dysfunction. This previous stage of the NF2 natural history study helped us understand how these symptoms arise even from very small or quiescent tumors. In the ongoing study we seek to find better ways to prevent hearing loss and counsel patients about speech and swallowing problems. Auditory testing will be performed annually for participants with measurable hearing. Participants with initially untreated vestibular schwannomas will be followed annually with vestibular testing. Speech and swallowing reassessments will be performed if worsening of speech or swallowing is reported. Blood will be collected at each visit for blood biomarker testing. This recent cohort will allow us to further explore the biologic basis for speech and swallowing dysfunction in patients with NF2. We will study and report the strength of association of MRI findings, clinical assessments cranial nerve deficits and speech/swallowing dysfunction. We hope to identify imaging biomarkers of hearing loss in NF2. We will also explore other aspects of NF2, including attempting to discover the mode of peripheral neuropathy in patients with NF2 and to discover previously unknown serum biomarkers associated with high tumor burden in NF2.